Mental retardation (MR) affects 2-3% of the population in the industrialized world, and remains a prevalent form of non-progressive cognitive impairment. Narrowly defined by an IQ of less than 70 and deficits in academic, adaptive, and interpersonal skills, disorders involving MR are, nonetheless, spread over a broad etiology, resulting from both genetic and non-genetic causes. The breadth and frequency of MR-related cognitive dysfunction is alarming considering that pharmacological intervention is currently non-existent.
Historically, neuroscientists have probed the brain in MR for clues to possible treatment strategies of MR-related learning difficulties. In the case of Down syndrome, these pioneering investigations have led to observations of tissue atrophy, white matter abnormalities, neuronal cell loss, stunted dendritic branching, and spine dysgenesis. Interestingly, many of the histological features noted in the brains of individuals with Down syndrome parallel phenotypes that have been found in the brains of individuals with other classes of MR, such as inborn errors of metabolism and non-genetic insults. Connections among different X-linked forms of MR have also been made, with disrupted synaptic structure, synaptic plasticity, and Ras-MAPK signaling as emerging themes. Similarities across the wide spectrum of MR-related disorders argue that common mechanisms underlie the manifestation of learning and memory deficits in intellectually handicapped children and young adults.
Down Syndrome (DS) is the most commonly occurring form of mental retardation in man, with an incidence of 1 in 600 births. The etiology surrounding the disorder was first described as a nondisjunctive error during meiosis of human chromosome 21 (hC21), resulting in the overexpression of an estimated 225 genes normally found on the chromosome. DS is characterized by congenital heart disease, endocrine disturbances, and immunologic deficiency, but is most universally marked by learning and memory difficulties in affected individuals that preclude adaptive cognitive and interpersonal function.
How the presence of hC21 genes in triplicate alters the maturation of the central nervous system (CNS) and subsequent cognitive development in DS has remained an open question. DS brains generally appear normal at birth. Newborns with DS exhibit typical brain weights, and do not exhibit any differences in gross neuronal and synaptic structure from children without the disorder. Quantitative analysis of DS prefrontal layer III pyramidal cells around birth and at 2.5 months of age indicates no differences in dendritic differentiation. Brain growth, in fact, proceeds normally for the first 5 to 6 months of life. However, soon after the infantile period (>6 months) the DS brain begins to show the abnormalities that characterize it in adulthood. The emergence of these cytological abnormalities may coincide with the beginning of IQ decline in DS-affected children within the first few years of life.
Investigation of CNS abnormalities and cognitive dysfunction in DS has been greatly facilitated by the development of two segmentally trisomic mouse models of DS: Ts65Dn and Ts1Cje. Ts65Dn mice are trisomic for segments of mouse chromosome 16 (Mmu 16) highly homologous to the long arm of hC21, including portions of the so-called DS “critical region.” Phenotypically, Ts65Dn mice faithfully recapitulate some of the most salient and fundamental features of DS. The topography of craniofacial maldevelopment in Ts65Dn mirrors that observed in DS patients; likewise, Ts65Dn mice exhibit similar patterns of cerebellar atrophy during early postnatal development. The utility of Ts65Dn as a mouse model of DS is strengthened further by findings that detail nearly comprehensive deficits in Ts65Dn short- and long-term spatial memory, working memory, and reference memory.
The treatment of mental retardation is of great clinical and humanitarian interest. The present invention addresses this issue.
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The synaptic connections in the Ts65Dn brain have been assessed by a variety of assays. For example, quantitative electron microscopy (EM) of Ts65Dn CNS has revealed a loss of asymmetric, excitatory synapses in Ts65Dn cortex relative to WT tissue, with a concurrent sparing of symmetric, inhibitory synapses (Kurt et al., 2000). Reductions in the density of excitatory synapses, and in the ratio of excitatory-to-inhibitory signaling in the Ts65Dn brain, have been noted alongside compensatory increases in the synaptic apposition lengths of asymmetric and symmetric synaptic junctions.
Recent studies using lucifer-yellow filling of neurons in Ts65Dn acute slices have indicated that a widening of synaptic clefts may relate to the development of enlarged spines in Ts65Dn cortex (see Belichenko et al. (2004) J Comp Neurol. 480(3):281-98). In an in vitro system, deficits in Ts65Dn hippocampal LTP were shown to reverse upon application of picrotoxin (see Kleschevnikov (2004) J Neurosci. 24(37):8153-60). Costa et al., (2005) Neur. Lett. 382:317-322 report deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse. Levkovitz et al. (1999) J. Neuroscience 19:10977-10984 discuss upregulation of GABA neurotransmission in the suppression of hippocampal excitability and prevention of long-term potentiation in transgenic superoxide dismutase-over-expressing mice.
It has been suggested that excessive immunoreactivity of the glutamine receptor GluR1 may be involved in degeneration of neurons and the early formation of senile plaques in Down syndrome, as tissue samples taken from the frontal lobes of patients with Down syndrome exhibit homeostatic elevations in GIuR1 immunoreactivity (Arai et al. (1996) Pediatr. Neurol. 15:203-206).
Ginkgo biloba extract was administered to two young patients with trisomy 21 (Donfrancesco et al. (2004) Phytomedicine 11:469. Pentylenetetrazol (metrazol) was administered to children with mental deficiencies by Berman et al. (1957) AMA Journal of Diseases of Children 94:231; and to psychogeriatric patients by Stotsky et al. (1972). GABAergic agonist (diazepam) drugs were administered to children with Down Syndrome by Cocchi (1985) Int. J. Psychosomatics 32:12-16 reducing depression.
Heteoaryl fused aminoalkyl-imidazole derivatives as selective modulators of GAGAA receptors are discussed in US Patent Application 2003/0092912. Use of GABA inverse agonists in combination with nicotine receptor partial agonist, estrogen, selective estrogen modulators or vitamin E is discussed in U.S. Patent Application 2004/0082555. Combination use of acetylcholinesterase inhibitors and GABAA inverse agonists for the treatment of cognitive disorders is discussed in U.S. Patent Application 2002/0151591. L-655,708 is reported to enhance cognition in rats but is not pro-convulsant at a dose selective for α5-containing GABAA receptors.